Metabolic syndrome is one of the rapid growing health problems and has been the major risk factor for both diabetes and cardiovascular disease (CVD). Both genetic and environmental factors play a role in the development of metabolic syndrome.
The metabolic syndrome represents a combined occurrence of atherogenic dyslipidemia, insulin resistance, hypertension and obesity. It is established that obesity and metabolic syndrome significantly influence the onset of cardiovascular disorders particularly in presence of type-2 diabetes mellitus. Increasing incidence of obesity has markedly enhanced the prevalence of metabolic syndrome world wide. Pro-inflammatory and pro-thrombotic state, responsible for endothelial dysfunction is a common feature among metabolic syndrome cases. In metabolic syndrome the status of impaired glucose tolerance, insulin resistance, dyslipidemia and hypertension exhibits a pro-thrombotic state.
It is reported that about one quarter of adults and about nine percent of teenagers are having metabolic syndrome. Persons with metabolic syndrome are two times more at risk of developing heart disease and five times at risk of developing diabetes. The etiopathogenesis of metabolic syndrome is both genetic and environmental factors. Excess abdominal fat, defect in insulin action and energy storage are the major risk factors playing role in the occurrence of metabolic syndrome. According to the National Cholesterol Education Program of Adult Treatment Panel III (ATP-III) guidelines for identifying metabolic syndrome, the diagnosis is based upon the involvement of three or more of the components together like abdominal obesity, triglycerides, HDL-c, blood pressure and fasting glucose level.
Obesity play a major role in the development of metabolic syndrome. Obesity results from an imbalance between energy intake and energy expenditure. Both genetic as well as environmental factors are the predisposing factor for weight grain and causing obesity. Obesity management requires a drastic pharmacotherapy due to unsatisfactory results of diet control and exercise. Recently the anti-obesity agent Sibutramine an appetite suppressant and Orlistat an inhibitor of fat absorption, is being used for the treatment of metabolic syndrome.
Maximum attention has been focused on the identification and treatment of dyslipidemia associated with metabolic syndrome. The abnormality in lipid metabolism with abdominal fat accumulation is well defined. An increased number of small dense LDL particles is constant feature of dyslipidemia of abdominal adiposity as they are associated with insulin resistance, intra-abdominal fat and hypertension. LDL comprises a spectrum of particles that vary in size, density, chemical composition and atherogenic potentials. The presence of small dense cholesterol-depleted LDL particles is associated with an increased risk of mycordial infarction and further worsens due to severity of cardiovascular disease. Due to the mechanism the small dense LDL particles enter in to the arterial wall more easily bind to arterial wall proteoglycans more avidly and are susceptible to oxidative modification, leading to macrophage uptake all of which may contributing to increased atherogenesis.
The evaluation of apolipo-B in the metabolic syndrome can help in targeting patients for aggressive lipid-lowering therapy. High levels of LDL-c are generally accepted to be one of the strongest risk factors for cardiovascular disease. Insulin resistance is associated with increased numbers of small VLDL-c and LDL-c particles, reflected by higher apolipo-B levels, with decreased triglyceride to apolipo-B ratios compared with those in individuals with normal insulin sensitivity. Studies have shown that increased apolipo-B and apolipo-B-containing lipoproteins (VLDL-c and LDL-c) are related to an increased risk of cardiovascular disease found significantly higher in individuals with metabolic syndrome.
Evidence suggests an association between chronic inflammation, insulin resistance, obesity, type-2 diabetes mellitus and arthrosclerosis. Recently, workers have reported that chronic inflammatory process may enhance insulin resistance and impaired β-cell function which are the risk factors for the occurrence of diabetes.
A number of studies have indicated that obesity and insulin resistance are associated with higher levels of markers of inflammation and endothelial function. Thus the relationship between various inflammatory markers particularly c-reactive protein and interleukin-6 and risk of development of type-2 diabetes mellitus is well established. Adiponectin i.e. adipocyte derived hormone has potentiality to down regulate inflammatory responses and also to improve glucose tolerance and insulin resistance. Adiponectin is related to insulin resistance and adiposity in humans and it is protective against the risk of development of diabetes.
Recently adiponectin has been discovered as a potential agent derived from adipose tissue. Low plasma levels of adiponectin are associated with insulin resistance, obesity, atherosclerosis, dyslipidemia and ultimately results in coronary heart disease. This hormone has been shown to be a key regulator of insulin sensitivity in human being. Adiponectin is an adipose tissues derived glycoprotein totally secreted by adipose tissue. Circulating adiponectin activates the peroxisome, proliferators activated receptor (PPAR-α) which are responsible for the regulation of glucose metabolism. Several workers have observed that hypo-adiponectenemia is a result of obesity induced, insulin resistance in adipose tissues. The molecular mechanism of insulin resistance specially in adipose tissues can only be understood from the study of endocrine regulation of energy metabolism and the role of various adipokines like leptin, ghrelin, adiponectin and resistin. All these adipokines are produced by adipose tissues. The biological effects of adiponectin in humans have been a subject of interests to the pharmacologist who are searching sub-specific targets who can regulate the abnormal anergy metabolism and can prevent the occurrence of insulin resistance, obesity and other related complications of metabolic syndrome. In case of insulin resistance plasma adiponectin is significantly less and is also associated with elevated levels of lipoprotein, glycemic index and dyslipidemia. It has been reported that adiponectin gene variants were one of the causes of obesity and insulin resistance.
The endothelial cells produce different variety of molecule that regulates its barrier function, and maintains the vascular homeostasis. From our observation it is apparent that the combined formulation specifically Dioscorea glabra maintains the vascular integrity by its local and central action. The Sphingosine-1-phosphate is derived from platelet and play an important role in maintaining endothelial barrier function which is one of the most complicated process.
There is an intimate association between obesity and inflammatory markers such as c-reactive protein (CRP) which has been repeatedly associated with increased risk of CVD. This association appears to mediate the progression to diabetes and CVD.
Insulin resistance may cause hypertension, however all patients with hypertension may not have metabolic abnormalities, nor does hypertension occur in all cases showing increased insulin level.
Further, reported that blood pressure falls when the dose of insulin is decreased in obese hypertensive patients with type-2 diabetes and increases when insulin treatment is begun in diabetic patients whose plasma glucose concentration are poorly controlled with oral agents.
The identification of large number of genetic markers particularly single nucleotide polymorphism is of clinical significance to launch preventive measures as well as to understand the susceptibility towards specific disease condition. The unsatisfactory achievements in the area of clinical diagnosis and therapy is due to insufficient studies on heterogeneity of human populations, late onset of diseases is of complex nature of disease and concomitant presence of confounding risk factors. Several genome scans have been carried out recently on metabolic syndrome. However, to identify disease genes and their etiologic genetic variants to explain disease phenotypes from biologic point of view is difficult. Many of these genes have been associated with metabolic syndrome in various ethnic populations. These candidate genes are mainly PPAR-γ, adiponectin, CD36, β-adrenergic receptors, insulin receptor, substrates, 11β-hydroxysteriod dehydrogenase type 1 (11β-HSD), CRP, TNF-α, calpain-10 (CAPN10), upstream transcription factor 1 and skeletal muscle glycogen synthase-1.
In brief, the adiponectin of susceptibility genes of metabolic syndrome and their, functional variants as well as the associated patho-physiological mechanisms are of importance as it makes us to design preventive strategies and targeted treatments.
Keeping the above facts in view it was proposed to develop a plant based safe drug beneficial in the management of cluster of clinical conditions i.e. obesity, insulin resistance, dyslipidemia, hypertension associated with metabolic syndrome. As all these are conventional CHD risk factors and aggregate at one place among individuals with metabolic syndrome are warranted for a drastic management strategy in order to prevent the risk of CHD mortality among metabolic syndrome patients.
Scientific evaluation of some of the Ayurvedic drugs have shown better efficacy over standard pharmacologic therapies with minimum or without any side effect. The successful management of metabolic syndrome is seldom possible with a single drug entity as it is a disease condition clustering a group of abnormalities. In Ayurvedic system of medicine a comprehensive description as well as prevention and management methods/procedures is given for obesity, diabetes and lipid disorders. Thus taking lead from Ayurvedic literature the present test formulation has been prepared and evaluated on scientific parameters involved with metabolic syndrome.